Human plasminogen, which functions to maintain blood fluidity by dissolving fibrin clots, is a protein with a molecular weight of 85,000 daltons. On activation, it is converted to plasmin, which consists of a heavy (MW 55,000 daltons) and a light (MW 25,000 daltons) chain connected by two disulfide bonds. The light chain is similar in sequence to trypsin and contains the active site. The function of the heavy chain is unknown. Recent sequence studies in this and other laboratories have shown that the heavy chain consists of five mutually homologous domains which are characterized by three inter-domain disulfide bonds. It is our goal to elucidate the structure of plasmin(ogen) and to learn how plasminogen interacts with other macromolecules in the fibrinolysis system. Since the primary structure is now almost completely known, we are attempting to obtain information about the the tertiary structure of the molecule by chemical modification of amino acids (lysine, tryosine, aspartic and glutamic acids) exposed on the surface. We are particularly interested to see whether the homologous domains, which have similar primary structures, have similar tertiary structures. Conventional forms of chemical modification will be used as well as some new methods we have devised, which utilize covalent chromatography to facilitate isolation of peptides containing modified amino acids. When we have learned some details of the topography of plasminogen, we plan to study the site of fibrin binding to plasminogen using chemical modification of fibrin-plasminogen complexes. BIBLIOGRAPHIC REFERENCES: H.M. Lee and R.A. Laursen, The Primary Structure of Human Plasminogen: Characterization and Alignment of the Cyanogen Bromide Peptides, FEBS Letters, 67, 113 (1976).